title: Novel selective quinazoline inhibitors of endothelin converting enzyme-1.
abstract: PD 069185 is a highly selective and structurally novel inhibitor of endothelin converting enzyme-1 (ECE-1). PD 069185 is a trisubstituted quinazoline with an IC50 value of 0.9 +/- 0.1 microns for inhibition of human ECE-1 from the solubilized membrane fraction of CHO cells stably transfected with human ECE-1 cDNA. Kinetic analysis revealed that PD 069185 is best fit with a competitive inhibition model with a Ki value of 1.1 +/- 0.1 microns and binds in a reversible manner. The closely related enzyme, ECE-2, is not inhibited at up to 100 microns PD 069185. In addition, PD 069185 at 200-300 microns has little effect on other metalloproteases, such as neutral endopeptidase 24.11, stromelysin, gelatinase A, and collagenase, showing a high ECE-1 specificity. Data are also presented to show that this series of inhibitors are effective in inhibiting ECE-1 in intact cells and in attenuating the increase in perfusion pressure induced by big ET-1 in isolated rat mesentery. These non-peptidic ECE-1 inhibitors should serve as a valuable tool to study the pathophysiological role of endothelin and the therapeutic potential of ECE-1 inhibitors.
authors.affiliation: Department of Biochemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. ahnk@aa.wl.com
authors.forename: K
authors.initials: K
authors.lastname: Ahn
authors.forename: A M
authors.initials: AM
authors.lastname: Sisneros
authors.forename: S B
authors.initials: SB
authors.lastname: Herman
authors.forename: S M
authors.initials: SM
authors.lastname: Pan
authors.forename: D
authors.initials: D
authors.lastname: Hupe
authors.forename: C
authors.initials: C
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Nikam
authors.forename: X M
authors.initials: XM
authors.lastname: Cheng
authors.forename: A M
authors.initials: AM
authors.lastname: Doherty
authors.forename: R L
authors.initials: RL
authors.lastname: Schroeder
authors.forename: S J
authors.initials: SJ
authors.lastname: Haleen
authors.forename: S
authors.initials: S
authors.lastname: Kaw
authors.forename: N
authors.initials: N
authors.lastname: Emoto
authors.forename: M
authors.initials: M
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008666:Metalloendopeptidases; D010477:Perfusion; D011312:Pressure; D011498:Protein Precursors / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; C110777:PD 069185; D011498:Protein Precursors; D011799:Quinazolines; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; C000606924:ECE2 protein, human; D000072396:Endothelin-Converting Enzymes